During the conversion of hepato-carcinogenic amines to excretable metabolites in liver cell, reactive electrophilic species may be generated which bind to protein and nucleotide bases, causing structural and functional disturbances which may induce cancerous states. The primary objective of this research is to test the hypothesis that the reactive electrophilic intermediate directly responsible for the cancer-inducing action of carcinogenic amines is generated in a reaction subsequent to the formation of N-hydroxylated amine metabolites. Hydroxylamines will be generated in liver homogenates by the hepato-enzymatic reduction of keto-oximes under anaerobic conditions. The hepatic oxime reductase(s) will be characterized and partially purified. Steady state kinetics of oxime reduction will be monitored using a high pressure liquid chromatographic separation of the substrate from its metabolites. Isotopically-labelled oxime substrates will be incubated with liver homogenates under anaerobic conditions to determine if hydroxylamines, generated during enzymatic reduction can generate electrophilic alkylating species, capable of binding with protein and polynucleotide bases. Studies will also be conducted to determine if oximes and/or their metabolic intermediates effect protein and polynucleotide biosynthesis by studying their effect on the incorporation of radioactively labelled amino acids into liver slices. Similarly, their effect on the rate of incorporation of isotopically- labelled orotic acid into RNA will also be studied. The metabolism of a series of acetophenone oxime derivatives will be studied to help determine the mechanism of reduction. The effect electron withdrawing and releasing moities exert on the rate of acetophenone oxime reduction will be investigated.